Abscisic acid (ABA, I) is a plant hormone that regulates diverse aspects of growth and development. In higher plants including seed germination and maturation, regulation of stomatal opening, root and shoot growth and transpiration. It also plays a role in plant tolerance and adaptation to environmental stresses such as drought, cold or excess salinity.
The two-dimensional structure of ABA (I) was first elucidated In the 1960's to be a monocyclic sesquiterpene and verified by its racemic synthesis (Ohkuma, K.; Addicott, F. T.; Smith, O. E.; Thiessen, W. E., Tetrahedron Letters 1965, 6 (29), 2529-2535). The absolute stereochemistry of ABA (I) was later determined to be S-ABA (I), as shown below (Ryback, G., Journal of the Chemical Society, Chemical Communications 1972, (21), 1190-1).

Plant receptors for ABA (I) have been elusive and have been identified only recently. ABA (I) may be applied externally to plants to provide certain desired effects such as maintaining dormancy of buds, improving thinning, accelerating defoliation or enhancing colour development of fruits. However, ABA (I) has found limited use as an externally applied plant growth regulator because it is easily catabollzed so that its effects are short-lived.
The principal catabolic pathway of ABA (I) in plants involves hydroxylation at the 8′-methyl carbon (following the conventional ABA numbering system) mediated by the enzyme P450 monooxygenase (+)-S-ABA 8′-hydroxylase. An intermediate, 8′-hydroxy ABA (II), is formed which undergoes reversible intramolecular Michael addition to form biologically inactive (−)-phaseic acid (III).

In recent years, synthetic analogues of ABA (I) have been developed with a view to designing compounds having greater potency and less susceptibility to catabolic degradation. Some features of the ABA molecule appear to be required for activity, particularly, the carboxyl and ketone groups, the six-membered ring, the 7′-methyl group and the 2-Z double bond of the side chain. Other parts of the molecule can be modified without a loss of activity. For example, the ring double bond, both the 8′- and 9′-methyl groups and the 4-E double bond of the side chain each can be altered and the resultant analogue retains activity.
Many synthetic analogues of ABA have been reported. For example, U.S. Pat. No. 6,004,905 discloses a family of 8′- and 9′-ABA analogues having a hydrocarbon group at the 8′- or 9′-position. Also disclosed is a method of synthesizing these analogues. US 2008/0200339 discloses bicyclic ABA analogues and a process for their production. Some of the varied analogues disclosed include hydroxylation at the C-8′ or C-9′ positions and a wide variety of substitutions at the C-8′ position.
Recently, it has been shown that replacing the 8′-methyl group of ABA with an acetylene group resulted in an analogue (compound (+)-(IV)) having 10 to 30 times greater anti-transperant and growth inhibition activities than natural ABA due to greater persistence in plants and weak irreversible inhibition of the enzyme (+)-S-ABA 8′-hydroxylase (Cutler, A. J, of al. (2000) Biochemistry. 39, 13614-13624. ).

Similarly, an 8′-cyclopropyl analogue (+)-(V) shows high biological activity.

Previously reported processes for synthesis of ABA and its analogues required eight distinct steps and eight separate work-up procedures. (Lei, of al. (1994) Phytochem. 37, 289-296.; Rose et al. (1997) Bioorg. Med. Chem. Lett. 7, 2543-2546.) As a result, the processes are costly and inefficient, and are not well adapted for use on an industrial scale. The previously reported process is as follows:

The first step in the previously reported synthetic process, production of 2,6-dimethyl-1,4-benzoquinone, mono ketal (VII), consisted of oxidation of 2,6-dimethylphenol (VI) using iodobenzene diacetate in ethylene glycol to give a monoketal protected benzoquinone (Lei, et al. (1994) Phytochem. 37, 289-296. ). This step has many drawbacks that render it unsuitable for use in an industrial process. It is difficult to scale-up on the bench top beyond 100 g. Furthermore, iodobenzene diacetate is too expensive to use for the synthesis of an agrochemical, which must be produced on an industrial scale. A byproduct of the reaction is a stoichiometric amount of iodobenzene that must be removed by distillation under reduced pressure. Also, the reaction generates a number of side products of the phenol that required column chromatography to remove. Accordingly, a need exists for a synthetic process having a more efficient and economical oxidation step.
The previously reported process also utilizes many discrete steps, which require the use of different reactants and different reaction vessels. Accordingly, a need exists for a simplified process which is suitably efficient to be used on an industrial scale.
Further, previously reported processes for synthesis of ABA and ABA analogues resulted in the manufacture of a racemic mixture (i.e. a 1:1 mixture containing both enantiomers of a chiral compound). A process for synthesis of racemic (±)-8′-acetylene ABA (±)-(IV) starting from two simple starting units (VII) and (VIII) has been previously reported, and is shown below (Rose et al. (1997) Bioorg. Med. Chem. Lett. 7, 2543-2546. ).

However, the enantiomer (−)-8′-acetylene ABA was shown to be biologically inactive as an agonist of ABA in studies. Therefore, the enantiomer (+)-8′-acetylene ABA is the biologically active stereoisomer (Cutler, A. J, et al. (2000) Biochemistry. 39, 13614-13624. ). Accordingly, an enantiomerically pure (+)-8′-acetylene ABA would provide a more potent form of the ABA analogue.
Accordingly, there remains a need for cost effective and efficient process for synthesis of ABA and ABA analogues, and for a process to synthesize enantiopure (+)-8′-acetylene ABA.